Exploring the effect of BRCA1/2 status on chemotherapy-induced hematologic toxicity in patients with ovarian cancer.

OBJECTIVE: BRCA1/2 are integral to the DNA repair mechanism and their germline pathogenic variants (gBRCA) result in a high risk for developing breast and ovarian cancer. Patients with gBRCA mutations showed increased sensitivity to DNA cross-linking agent but might have increased treatment-related toxicities. Thus, we hypothesized that gBRCA mutation ovarian cancer patients who underwent platinum-based chemotherapy might be at higher risk of developing chemotherapy-induced hematologic toxicity. METHODS: This study enrolled 160 patients with ovarian cancer who received frontline platinum-based chemotherapy between 2011 and 2019 in Kyungpook National University Chilgok Hospital. Incidence rate and severity of chemotherapy-induced hematologic toxicity (neutropenia, anemia, thrombocytopenia) was compared for BRCA mutation and wild patients. RESULTS: 160 women, including 62 BRCA1/2 (38 BRCA1, and 25 BRCA2) mutation group, and 98 noncarriers, were analyzed. A higher frequency of G2 anemia was noted in the BRCA -mutant group (22% vs. 1%, p = 0.07). Furthermore, G3 anemia was significantly common among BRCA group (12.9% vs. 3%, p = 0.02). In the subgroup analysis according to BRCA1/2 status, BRCA1 mutated patients showed a significantly higher frequency of G1 anemia than BRCA2 (89% vs. 60%, p = 0.01). In terms of neutropenia and thrombocytopenia, BRCA mutated patients and noncarriers had similar hematologic toxicity. CONCLUSION: Germline BRCA mutations were associated with a higher frequency of G2/3 anemia in ovarian cancer patients who underwent first-line platinum-based chemotherapy. Moreover, the BRCA1 mutation appeared to be more strongly associated with the incidence of chemotherapy-induced anemia. Our findings warrant further investigation in larger, prospective studies to confirm these current findings and determine whether preventive interventions may be necessary.

Long non-coding RNA SOX2OT in tamoxifen-resistant breast cancer.

Hormone receptor (HR)-positive breast cancer can become aggressive after developing hormone-treatment resistance. This study elucidated the role of long non-coding RNA (lncRNA) SOX2OT in tamoxifen-resistant (TAMR) breast cancer and its potential interplay with the tumor microenvironment (TME). TAMR breast cancer cell lines TAMR-V and TAMR-H were compared with the luminal type A cell line (MCF-7). LncRNA expression was assessed via next-generation sequencing, RNA extraction, lncRNA profiling, and quantitative RT-qPCR. SOX2OT overexpression effects on cell proliferation, migration, and invasion were evaluated using various assays. SOX2OT was consistently downregulated in TAMR cell lines and TAMR breast cancer tissue. Overexpression of SOX2OT in TAMR cells increased cell proliferation and cell invasion. However, SOX2OT overexpression did not significantly alter SOX2 levels, suggesting an independent interaction within TAMR cells. Kaplan-Meier plot analysis revealed an inverse relationship between SOX2OT expression and prognosis in luminal A and B breast cancers. Our findings highlight the potential role of SOX2OT in TAMR breast cancer progression. The downregulation of SOX2OT in TAMR breast cancer indicates its involvement in resistance mechanisms. Further studies should explore the intricate interactions between SOX2OT, SOX2, and TME in breast cancer subtypes.

Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer.

PURPOSE: In our previous study, Developmental endothelial locus-1 (Del-1) was a promising predictive marker for breast cancer. However, the downstream targets of Del-1 remain unknown. Here, we sought to discover a druggable target downstream of Del-1 and investigate the mechanism by which it regulates the course of breast cancer. METHODS: To investigate Del-1 downregulation effect on breast cancer, we performed transcriptome analysis using RNA sequencing of Del-1 knockdowned MDA-MB-231 cell line Plus, to investigate the expression of Del-1 and Maternal embryonic leucine zipper kinase (MELK), mRNA levels in eight different triple-Negative Breast Cancer (TNBC) cell lines were analyzed. High-throughput sequencing was performed on total RNA isolated. OTS167 was used for MELK inhibition. The effects of MELK on cell proliferation and invasion were determined using the MTT and Matrigel transwell assays. Furthermore, we examined MELK expression in breast cancer tissue. RESULTS: Del-1 and MELK mRNA expression levels were significantly higher in the TNBC cell lines, MDA-MB-468, HCC-1806, and MBA-MB-231. Knocking down Del-1 with siRNA in HCC-1806 and MBA-MB-231 cells significantly decreased MELK expression and thus suggested a possible relationship between Del-1 and MELK. In MDA-MB-468 cells, a basal-like 1 TNBC cell line, OTS167 significantly inhibited breast cancer cell proliferation and promoted cell apoptosis. To further investigate the relationship between Del-1 and MELK, dual inhibition of both Del-1 and MELK was performed, which significantly reduced the viability of MDA-MB-468 and MBA-MB-231 cells. CONCLUSION: We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Effectiveness of Carboplatin-Prescreening Intradermal Skin Tests to Reduce Unanticipated Immediate Hypersensitivity Reactions: A Comparative Study.

BACKGROUND: Carboplatin administration poses a risk of immediate hypersensitivity reactions (IHRs) that tend to increase with repeated administration and are mostly IgE-mediated. OBJECTIVE: This study evaluated the usefulness of carboplatin-prescreening intradermal skin tests (IDTs). METHODS: Carboplatin-prescreening IDTs were routinely conducted in patients with a history of receiving six or more carboplatin cycles beginning in January 2021. The primary objective was to assess disparities in the incidence of unanticipated IHRs to carboplatin administration. We compared patients in the intervention group (from 2021 to 2022) and those who did not undergo prescreening IDTs under the same conditions (preintervention group, from 2019 to 2020). Secondary objectives included evaluating the sensitivity and specificity of the prescreening IDT and the incidence of carboplatin IHR according to the number of infusion cycles. RESULTS: The intervention group was composed of 67 patients who were administered 347 carboplatin cycles whereas the preintervention group included 96 patients who were administered 464 carboplatin cycles. The risk of unanticipated carboplatin IHRs decreased by 83.2% in the intervention group compared with results in the preintervention group (preintervention group, 3.45%, n = 16 vs intervention group, 0.58%, n = 2; P = .005). The prescreening IDT showed a sensitivity and specificity of 77.78% and 99.41%, respectively. The risk of newly developed IHRs based on the number of carboplatin cycles was less than 1% (cycles 1-5), 2.11% (cycle 6), 3.90% (cycles 7-12), 2.90% (cycles 13-18), and 0.74% (cycles 19 and greater), respectively. CONCLUSIONS: Initiating carboplatin-prescreening IDTs from the seventh cycle on significantly reduced the risk of unanticipated IHRs.

Centrosome clustering control in osteoclasts through CCR5-mediated signaling.

Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to and from the resorbing bone surface. However, the regulatory mechanisms and pathophysiological relevance of these processes remain largely unexplored. Bone histomorphometric analyses in Ccr5-deficient mice showed abnormalities in the morphology and functional phenotype of their osteoclasts, compared to wild type mice. We observed disorganized clustering of nuclei, as well as centrosomes that organize the microtubule network, which was concomitant with impaired cathepsin K secretion in cultured Ccr5-deficient osteoclasts. Intriguingly, forced expression of constitutively active Rho or Rac restored these cytoskeletal phenotypes with recovery of cathepsin K secretion. Furthermore, a gene-disease enrichment analysis identified that PLEKHM1, a responsible gene for osteopetrosis, which regulates lysosomal trafficking in osteoclasts, was regulated by CCR5. These experimental results highlighted that CCR5-mediated signaling served as an intracellular organizer for centrosome clustering in osteoclasts, which was involved in the pathophysiology of bone metabolism.

Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorder.

BACKGROUND: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members. METHODS: We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE. FINDINGS: Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P < 5.27 × 10-11), 44 of which were not observed in the PLHD group. Plasma glutamine levels were found to be associated with variants in the NLGN1 gene, a gene that encodes post-synaptic cell-adhesion molecules in excitatory neurons. This association was not detected in the PLHD group. Notably, a significant negative correlation between plasma glutamine and glutamate levels was observed in the AGRE group, but not in the PLHD group. Furthermore, plasma glutamine levels showed a negative correlation with the severity of restrictive and repetitive behaviours (RRB) in ASD, although no direct association was observed between RRB severity and the NLGN1 genotype. INTERPRETATION: Our findings suggest that plasma glutamine levels could potentially serve as an endophenotype, thus establishing a link between the genetic risk associated with NLGN1 and the severity of RRB in ASD. This identified association could facilitate the development of novel therapeutic targets, assist in selecting specific cohorts for clinical trials, and provide insights into target symptoms for future ASD treatment strategies. FUNDING: This work was supported by the National Institute of Health (grant numbers: R01MH107205, U01TR002623, R24OD024622, OT2OD032720, and R01NS129188) and the PrecisionLink Biobank for Health Discovery at Boston Children's Hospital.

Chylothorax associated with primary membranous nephropathy: a case report.

BACKGROUND: Chylothorax is a state in which pleurisy is induced by chylomicron leakage due to lymphatic injury. Membranous nephropathy (MN) is one of the relatively common glomerular diseases that cause nephrotic syndrome in adults. Chylothorax at the onset of nephrotic syndrome is very rare in adult patients. CASE DESCRIPTION: We report a case of chylothorax associated with primary MN. A 64-year-old man visited the hospital complaining of lower extremity edema and dyspnea for 4 weeks. Laboratory findings showed no azotemia but hypercholesterolemia, hypoalbuminemia, nephrotic-range proteinuria, and microscopic hematuria. Chest and abdominal computed tomography (CT) revealed no ascites, venous thrombosis, or malignancy with the presence of right-side pleurisy. Biochemical analysis of the pleural fluid was consistent with chylothorax. The patient was confirmed to have MN by percutaneous kidney biopsy. An angiotensin receptor blocker, diuretics, and a hypolipidemic agent were prescribed; non-per os, total parenteral nutrition (TPN), and subcutaneous injection of octreotide were added for management of chylothorax. As serum anti-phospholipase receptor 2 antibody (Ab) concentration increased again, immunosuppressive therapy (IST) consisting of alternating monthly cycles of glucocorticoids and oral cyclophosphamide was instituted. With no improvement in chylothorax and deteriorating nutritional status despite 3 weeks of medical therapy, lymphangiography was performed, followed by thoracic duct embolization (TDE). The patient was discharged from the hospital on day 53 with clinical improvement. At 9 months after discharge, clinical remission of primary MN was achieved without recurrence of chylothorax. CONCLUSIONS: Patients with nephrotic syndrome may rarely exhibit refractory chylothorax without chylous ascites, increasing the risk of serious metabolic complications such as severe malnutrition. Therefore, upon confirming chylothorax associated with primary nephrotic syndrome, prompt radiologic intervention for lymphatic leakage must be considered in addition to specific IST.

Treatment outcomes of advanced/metastatic extramammary Paget's disease in Korean patients: KCSG-RC20-06.

BACKGROUND: Extramammary Paget's disease (EMPD) is rare. There are no standard treatments due to its rarity and few clinical trials. METHODS: The objective of this multicenter study was to investigate treatment outcomes of Korean patients with advanced/metastatic EMPD. Data were collected retrospectively from 14 institutions participating in Korean Cancer Study Group (KCSG) Rare Cancer Committee. RESULTS: A total of 37 patients were identified. Of these 37 patients, 6 received locoregional therapy as a first-line treatment. In 31 patients who received systemic chemotherapy as a first-line treatment, platinum-based chemotherapy (n = 22) achieved an objective response rate (ORR) of 45.5% and a median progression-free survival (PFS) of 7.89 months. Taxane-based chemotherapy (n = 8) achieved an objective response rate of 62.5% and median PFS of 9.73 months. In second-line chemotherapy, platinum-based chemotherapy (n = 4) had a disease control rate (DCR) of 75.0% and median PFS of 3.45 months. Taxane-based chemotherapy (n = 8) had a DCR of 75.0% and a median PFS of 8.67 months. Six patients received anti-human epidermal growth factor receptor 2 (HER2) antibody during first- and second-line chemotherapy. Overall, systemic chemotherapy combined with anti-HER2 antibody had an ORR of 100% and a median PFS of 13.31 months. The ORR and PFS with systemic chemotherapy combined with trastuzumab was better than platinum- and taxane-based chemotherapy only. CONCLUSIONS: Due to its rarity, advanced or metastatic EMPD still has no established standard treatment. Results of our study indicate that the combination of trastuzumab with taxane has longer survival than trastuzumab monotherapy or conventional platinum- or taxane-based chemotherapy.

Implant-associated biofilm infection established in an experimental Galleria mellonella model.

The study reports in vivo biofilm infection implemented in an insect model. We mimicked implant-associated biofilm infections in Galleria mellonella larvae using toothbrush bristles and methicillin-resistant Staphylococcus aureus (MRSA). In vivo biofilm formation on bristle was achieved by sequentially injecting a bristle and MRSA into the larval hemocoel. It was found that biofilm formation was in progress without any external sign of infection in most of the bristle-bearing larvae for 12 h after MRSA inoculation. Whereas the activation of the prophenoloxidase system did not affect the preformed in vitro MRSA biofilms, an antimicrobial peptide interfered with in vivo biofilm formation when injected into bristle-bearing larvae infected with MRSA. Finally, our confocal laser scanning microscopic analysis revealed that the biomass of the in vivo biofilm is greater compared to that of the in vitro biofilm and harbors a distribution of dead cells, which might be bacteria and/or host cells.

ADGR: Admixture-Informed Differential Gene Regulation.

The regulatory elements in proximal and distal regions of genes are involved in the regulation of gene expression. Risk alleles in intronic and intergenic regions may alter gene expression by modifying the binding affinity and stability of diverse DNA-binding proteins implicated in gene expression regulation. By focusing on the local ancestral structure of coding and regulatory regions using the paired whole-genome sequence and tissue-wide transcriptome datasets from the Genotype-Tissue Expression project, we investigated the impact of genetic variants, in aggregate, on tissue-specific gene expression regulation. Local ancestral origins of the coding region, immediate and distant upstream regions, and distal regulatory region were determined using RFMix with the reference panel from the 1000 Genomes Project. For each tissue, inter-individual variation of gene expression levels explained by concordant or discordant local ancestry between coding and regulatory regions was estimated. Compared to European, African descent showed more frequent change in local ancestral structure, with shorter haplotype blocks. The expression level of the Adenosine Deaminase Like (ADAL) gene was significantly associated with admixed ancestral structure in the regulatory region across multiple tissue types. Further validations are required to understand the impact of the local ancestral structure of regulatory regions on gene expression regulation in humans and other species.

The impact of quality of life measured by WHOQOL-BREF on mortality in maintenance hemodialysis patients: a single center retrospective cross-sectional study.

BACKGRUOUND: Several previous studies have reported that quality of life (QoL) in hemodialysis patients affects mortality. However, the 36-item Short Form Health Survey, which has been used mainly in previous studies, is complicated in terms of questionnaire composition and interpretation. This study aimed to identify the impact of QoL on mortality in hemodialysis patients using an easier and simpler diagnostic tool. METHODS: This retrospective study included 160 hemodialysis patients. QoL was evaluated using the World Health Organization Quality of Life Questionnaire-Brief version (WHOQOL-BREF). Psychosocial factors were evaluated using the Hospital Anxiety and Depression Scale, Multidimensional Scale of Perceived Social Support, Montreal Cognitive Assessment, and Pittsburgh Sleep Quality Index. We also evaluated medical factors, such as dialysis adequacy and laboratory results. RESULTS: The mean hemodialysis vintage was 70.7±38.0 months. The proportion of patients who were elderly was higher in the mortality group than in the surviving group, and the Charlson Comorbidity Index score was also higher in the former group. Of the four domains of the WHOQOL-BREF, the physical health and psychological scores of the mortality group were significantly lower than those of the survival group. When the score in the physical health domain or psychological domain was ≤10, the 10-year mortality rate after hemodialysis initiation increased by approximately 2.3- and 2-fold, respectively. CONCLUSION: QoL may have a significant effect on mortality in patients undergoing hemodialysis. The WHOQOL-BREF is an instrument that can measure QoL relatively easily and can be used to improve the long-term prognosis of patients undergoing hemodialysis.

Investigating the Influence of PbS Quantum Dot-Decorated TiO2 Photoanode Thickness on Photoelectrochemical Hydrogen Production Performance.

To maximize the photoelectrochemical (PEC) hydrogen production performance of quantum dot (QD)-decorated photoelectrodes, it is crucial to prioritize the optimization of electrode's structure, including thickness and porosity. In this study, we prepare PbS QD-decorated mesoporous TiO2 photoanodes for PEC hydrogen production, and systematically investigate the influence of the photoanode thickness on optical properties and PEC performances. As the thickness of photoanodes increases from 6.4 µm to 16.3 µm, the light absorption capability is enhanced across the entire visible and near-infrared (IR) spectrum due to the improved loading of PbS QDs. However, the photocurrent density is optimized for the 11.9 µm thick photoanode (15.19 mA/cm2), compared to the 6.4 µm thick (10.80 mA/cm2) and 16.3 µm thick photoanodes (11.93 mA/cm2). This optimization is attributed to the trade-off between the light absorption capability and the efficient mass transfer of the electrolyte as the photoanode thickness increases, which is confirmed by the lowest charge transfer resistance (Rct) evaluated from the electrochemical impedance data.

Comprehensive characterization of putative genetic influences on plasma metabolome in a pediatric cohort.

BACKGROUND: The human exposome is composed of diverse metabolites and small chemical compounds originated from endogenous and exogenous sources, respectively. Genetic and environmental factors influence metabolite levels, while the extent of genetic contributions across metabolic pathways is not yet known. Untargeted profiling of human metabolome using high-resolution mass spectrometry (HRMS) combined with genome-wide genotyping allows comprehensive identification of genetically influenced metabolites. As such previous studies of adults discovered and replicated genotype-metabotype associations. However, these associations have not been characterized in children. RESULTS: We conducted the largest genome by metabolome-wide association study to date of children (N = 441) using 619,688 common genetic variants and 14,342 features measured by HRMS. Narrow-sense heritability (h2) estimates of plasma metabolite concentrations using genomic relatedness matrix restricted maximum likelihood (GREML) method showed a bimodal distribution with high h2 (> 0.8) for 15.9% of features and low h2 (< 0.2) for most of features (62.0%). The features with high h2 were enriched for amino acid and nucleic acid metabolism, while carbohydrate and lipid concentrations showed low h2. For each feature, a metabolite quantitative trait loci (mQTL) analysis was performed to identify genetic variants that were potentially associated with plasma levels. Fifty-four associations among 29 features and 43 genetic variants were identified at a genome-wide significance threshold p < 3.5 × 10-12 (= 5 × 10-8/14,342 features). Previously reported associations such as UGT1A1 and bilirubin; PYROXD2 and methyl lysine; and ACADS and butyrylcarnitine were successfully replicated in our pediatric cohort. We found potential candidates for novel associations including CSMD1 and a monostearyl alcohol triglyceride (m/z 781.7483, retention time (RT) 89.3 s); CALN1 and Tridecanol (m/z 283.2741, RT 27.6). A gene-level enrichment analysis using MAGMA revealed highly interconnected modules for dADP biosynthesis, sterol synthesis, and long-chain fatty acid transport in the gene-feature network. CONCLUSION: Comprehensive profiling of plasma metabolome across age groups combined with genome-wide genotyping revealed a wide range of genetic influence on diverse chemical species and metabolic pathways. The developmental trajectory of a biological system is shaped by gene-environment interaction especially in early life. Therefore, continuous efforts on generating metabolomics data in diverse human tissue types across age groups are required to understand gene-environment interaction toward healthy aging trajectories.

Oncologic necessity for the complete removal of residual microcalcifications after neoadjuvant chemotherapy for breast cancer.

The surgical range of breast cancer that shows pathologic complete response (pCR) without change in microcalcifications after neoadjuvant chemotherapy (NAC) is controversial. This study examined whole breast specimens to evaluate the necessity of mastectomy in those cases. The viability of cancer cells around the residual microcalcification was assessed using prospectively collected breast samples to confirm the presence or absence of cancer cells. A total of 144 patients with breast cancer and diffuse microcalcifications were classified into the reduced mass with no change in residual microcalcification (RESMIN, n = 49) and non-RESMIN (n = 95) groups. Five specimens were prospectively evaluated to assess the presence of viable cancer cells around the microcalcification. Tumor responses to NAC were significantly better with high pCR rates in the RESMIN group (p = 0.005 and p = 0.002). The incidence of human epidermal growth factor receptor 2-positive and triple-negative breast cancers was significantly high in the RESMIN group (p = 0.007). Although five (10.2%) patients had locoregional recurrence in the RESMIN group, no local recurrence in the breast was reported. Although pCR was highly estimated, residual cancers, including ductal carcinoma in situ, remained in 80% cases. Therefore, given the weak scientific evidence available currently, complete removal of residual microcalcifications should be considered for oncologic safety.

Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder.

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p < 5 × 10-7. Of note, the Stereotyped Behaviors and Restricted Interests total score in Autism Diagnostic Observation Schedule Module 3 was significantly associated with multiple variants in the VPS13B gene, a causal gene for Cohen syndrome and a candidate gene for syndromic ASD. Our findings yielded loci with small effect sizes due to the moderate sample size and, thus, require validation in another cohort. Nonetheless, our endophenotype-wide association analysis extends previous candidate gene discovery in the context of genotype and endophenotype association. As a result, these candidate genes may be responsible for specific traits that constitute core symptoms and neurocognitive function of ASD rather than the disorder itself.

Investigation of Anti-Liver Cancer Activity of the Herbal Drug FDY003 Using Network Pharmacology.

Globally, liver cancer (LC) is the sixth-most frequently occurring and the second-most fatal malignancy, responsible for 0.83 million deaths annually. Although the application of herbal drugs in cancer therapies has increased, their anti-LC activity and relevant mechanisms have not been fully studied from a systems perspective. To address these issues, we conducted a system-perspective network pharmacological investigation into the activity and mechanisms underlying the action of the herbal drug. FDY003 reduced the viability of human LC treatment. FDY003 reduced the viability of human LC cells and elevated their chemosensitivity. There were a total of 16 potential bioactive chemical components in FDY003 and they had 91 corresponding targets responsible for the pathological processes in LC. These FDY003 targets were functionally involved in regulating the survival, proliferation, apoptosis, and cell cycle of LC cells. Additionally, we found that FDY003 may target key signaling cascades connected to diverse LC pathological mechanisms, namely, PI3K-Akt, focal adhesion, IL-17, FoxO, MAPK, and TNF pathways. Overall, this study contributed to integrative mechanistic insights into the anti-LC potential of FDY003.

Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome.

Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies. The development of effective pharmacotherapies has been limited, in part, by lack of clarity about the pathobiology of pediatric ARDS. Epithelial lung injury, vascular endothelial activation, and systemic immune activation are putative drivers of this complex disease process. Prior studies have used either hypothesis-driven (e.g., candidate genes and proteins, in vitro investigations) or unbiased (e.g., genome-wide association, transcriptomic, metabolomic) approaches to predict clinical outcomes and to define subphenotypes. Advances in multiple omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have permitted more comprehensive investigation of PARDS pathobiology. However, omics studies have been limited in children compared to adults, and analyses across multiple tissue types are lacking. Here, we synthesized existing literature on the molecular mechanism of PARDS, summarized our interrogation of publicly available genomic databases to determine the association of candidate genes with PARDS phenotypes across multiple tissues and cell types, and integrated recent studies that used single-cell RNA sequencing (scRNA-seq). We conclude that novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.

Comparative Study Between Radioisotope Uptake and Fluorescence Intensity of Indocyanine Green for Sentinel Lymph Node Biopsy in Breast Cancer.

Recently, several breast surgeons have reported a new method for sentinel lymph node biopsy (SLNB) by using indocyanine green (ICG) with infrared camera. This study aimed to determine whether the lymph nodes (LNs) with ICG uptake are true SLNs and to assess the reliability of using only ICG for SLNB. Data were prospectively collected between April and September 2021. All palpable LNs were fat-trimmed and ordered from high to low signal of the gamma detector. The degree of radioisotope uptake and brightness of ICG staining of the axillary LNs detected with a fluorescent camera were compared and associated factors were analyzed. Discordance was defined as sentinel LNs (SLNs) showing a single uptake of radioisotope or fluorescence of ICG only, or when the orders of uptake and intensity degree were different between the 2 materials. A total of 79 SLNBs were performed on 78 patients with breast cancer. The breast cancer was classified as cTis-2N0-1. The discordance rate was 14/79 (17.7%) overall and 45/270 (16.7%) of the total retrieved axillary LNs. The first SLNs showed the lowest discordance rate of 6.3%, whereas the second and third SLNs showed higher discordance rates of 27.6% and 60.0%, respectively. There were no associated clinicopathologic factors that affected the discordance between uptake of radioisotope and fluorescence intensity of ICG. The use of ICG alone for SLNB may be insufficient because of the high discordance rates between radioisotopes and ICG uptake. However, the first SLN could be cautiously regarded as a true SLN.